Identification of a large anion channel required for digestive vacuole acidification and amino acid export in Plasmodium falciparum.

IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences
Gagandeep S Saggu, Jinfeng Shao, Mansoor A Siddiqui, Maria Traver, Tatiane Macedo-Silva, Joseph Brzostowski, Sanjay A Desai
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引用次数: 0

Abstract

Malaria parasites survive in human erythrocytes by importing and digesting hemoglobin within a specialized organelle, the digestive vacuole (DV). Although chloroquine and other antimalarials act within the DV, the routes used by drugs, ions, and amino acids to cross the DV membrane remain poorly understood. Here, we used single DV patch-clamp to identify a novel large conductance anion channel as the primary conductive pathway on this organelle in Plasmodium falciparum, the most virulent human pathogen. This Big Vacuolar Anion Channel (BVAC) is primarily open at the DV resting membrane potential and undergoes complex voltage-dependent gating. Ion substitution experiments implicate promiscuous anion flux with Cl- being the primary charged substrate under physiological conditions. Conductance and gating are unaffected by antimalarials targeting essential DV activities and are conserved on parasites with divergent drug susceptibility profiles, implicating an unexploited antimalarial target. A conditional knockdown strategy excluded links to PfCRT and PfMDR1, two drug-resistance transporters with poorly defined transport activities. We propose that BVAC functions to maintain electroneutrality during H+ uptake, allowing DV acidification and efficient hemoglobin digestion. The channel also facilitates amino acid salvage, providing essential building blocks for parasite growth. Direct transport measurements at the DV membrane provide foundational insights into vacuolar physiology, should help clarify antimalarial action and drug resistance, and will guide therapy development against the parasite's metabolic powerhouse.

恶性疟原虫消化液泡酸化和氨基酸输出所需的大阴离子通道的鉴定。
疟原虫通过在一个特殊的细胞器——消化液泡(DV)内输入和消化血红蛋白,在人红细胞中存活。虽然氯喹和其他抗疟药物在DV内起作用,但药物、离子和氨基酸通过DV膜的途径仍然知之甚少。在这里,我们使用单DV膜片钳鉴定了一个新的大电导阴离子通道作为恶性疟原虫细胞器上的主要导电途径,恶性疟原虫是最致命的人类病原体。这个大液泡阴离子通道(BVAC)主要在DV静息膜电位下开放,并经历复杂的电压依赖性门控。离子取代实验表明在生理条件下Cl-是主要带电底物的混杂阴离子通量。电导和门控不受针对基本DV活性的抗疟药物的影响,并且在具有不同药物敏感性谱的寄生虫上是保守的,这意味着一个未开发的抗疟靶点。条件敲低策略排除了PfCRT和PfMDR1的连接,这两种耐药转运蛋白的转运活性不明确。我们提出BVAC的功能是在H+摄取过程中维持电中性,从而允许DV酸化和有效的血红蛋白消化。该通道还促进氨基酸的回收,为寄生虫的生长提供必要的基础。DV膜上的直接运输测量为液泡生理学提供了基础见解,应该有助于阐明抗疟作用和耐药性,并将指导针对寄生虫代谢动力的治疗开发。
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来源期刊
PLoS Biology
PLoS Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-BIOLOGY
CiteScore
15.40
自引率
2.00%
发文量
359
审稿时长
3-8 weeks
期刊介绍: PLOS Biology is the flagship journal of the Public Library of Science (PLOS) and focuses on publishing groundbreaking and relevant research in all areas of biological science. The journal features works at various scales, ranging from molecules to ecosystems, and also encourages interdisciplinary studies. PLOS Biology publishes articles that demonstrate exceptional significance, originality, and relevance, with a high standard of scientific rigor in methodology, reporting, and conclusions. The journal aims to advance science and serve the research community by transforming research communication to align with the research process. It offers evolving article types and policies that empower authors to share the complete story behind their scientific findings with a diverse global audience of researchers, educators, policymakers, patient advocacy groups, and the general public. PLOS Biology, along with other PLOS journals, is widely indexed by major services such as Crossref, Dimensions, DOAJ, Google Scholar, PubMed, PubMed Central, Scopus, and Web of Science. Additionally, PLOS Biology is indexed by various other services including AGRICOLA, Biological Abstracts, BIOSYS Previews, CABI CAB Abstracts, CABI Global Health, CAPES, CAS, CNKI, Embase, Journal Guide, MEDLINE, and Zoological Record, ensuring that the research content is easily accessible and discoverable by a wide range of audiences.
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